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US-12624114-B2 - Method of reducing serum amyloid A (SAA) protein levels in a patient by administering an interleukin-33 (IL-33) antibody

US12624114B2US 12624114 B2US12624114 B2US 12624114B2US-12624114-B2

Abstract

The present invention provides methods for treating inflammatory diseases, or conditions associated with, or resulting in part from, elevated levels of IL-33 and IL-4, in particular inflammatory lung disorders. The methods of the present invention comprise administering to a subject in need thereof one or more therapeutically effective doses of an IL-33 antagonist alone or in combination with one or more therapeutically effective doses of an IL-4R antagonist. In certain embodiments, the methods of the present invention include use of the antagonists to treat any inflammatory disease or condition mediated in part by enhanced IL-33-mediated signaling and IL-4-mediated signaling.

Inventors

  • Jamie M. Orengo
  • Jeanne ALLINNE
  • Andrew J. Murphy
  • George D. Yancopoulos

Assignees

  • REGENERON PHARMACEUTICALS, INC.

Dates

Publication Date
20260512
Application Date
20231129

Claims (17)

  1. 1 . A method for reducing serum amyloid A (SAA) protein levels in a subject in need thereof, the method comprising administering an interleukin-33 (IL-33) antibody or antigen-binding fragment thereof to the subject, wherein the IL-33 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising three heavy chain complementarity determining regions, HCDR1, HCDR2, and HCDR3, comprising the amino acid sequences of SEQ ID NOs: 276, 278, and 280, respectively, and a light chain variable region (LCVR) comprising three light chain complementarity determining regions, LCDR1, LCDR2, and LCDR3, comprising the amino acid sequences of SEQ ID NOs: 284, 286, and 288, respectively.
  2. 2 . The method of claim 1 , wherein the subject in need thereof has an inflammatory disease or disorder.
  3. 3 . The method of claim 1 , wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 274.
  4. 4 . The method of claim 1 , wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 282.
  5. 5 . The method of claim 1 , wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 274 and the LCVR comprises the amino acid sequence of SEQ ID NO: 282.
  6. 6 . The method of claim 1 , wherein the IL-33 antibody or antigen-binding fragment thereof is the IL-33 antibody designated REGN3500.
  7. 7 . The method of claim 1 , wherein the IL-33 antibody or antigen-binding fragment thereof is administered to the subject subcutaneously, intravenously, intramuscularly, or intranasally.
  8. 8 . The method of claim 7 , wherein the IL-33 antibody is administered to the subject subcutaneously.
  9. 9 . The method of claim 7 , wherein the IL-33 antibody is administered to the subject intravenously.
  10. 10 . The method of claim 2 , wherein the inflammatory disease or disorder is an inflammatory lung disease or disorder.
  11. 11 . The method of claim 10 , wherein the inflammatory lung disease or disorder is asthma, chronic obstructive pulmonary disease (COPD), or chronic bronchitis.
  12. 12 . The method of claim 2 , wherein the inflammatory disease or disorder is chronic rhinosinusitis with or without nasal polyps.
  13. 13 . The method of claim 2 , wherein the inflammatory disease or disorder is inflammatory bowel disease, Crohn's disease, or ulcerative colitis.
  14. 14 . The method of claim 1 , further comprising administering an effective amount of one or more additional therapeutic agents.
  15. 15 . The method of claim 11 , wherein the inflammatory disease or disorder is chronic obstructive pulmonary disease (COPD).
  16. 16 . The method of claim 12 , wherein the inflammatory disease or disorder is chronic rhinosinusitis with nasal polyps.
  17. 17 . The method of claim 12 , wherein the inflammatory disease or disorder is chronic rhinosinusitis without nasal polyps.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 17/028,011, filed Sep. 22, 2020, now U.S. Pat. No. 11,866,503, which is a continuation of U.S. application Ser. No. 15/827,357, filed Nov. 30, 2017, now U.S. Pat. No. 10,815,305, which claims the benefit under 35 USC § 119 (e) of U.S. Provisional Application Nos. 62/428,634, filed Dec. 1, 2016, 62/473,738, filed Mar. 30, 2017, and 62/567,318, filed Oct. 3, 2017, all of which are herein specifically incorporated by reference in their entireties. REFERENCE TO A SEQUENCE LISTING This application incorporates by reference the sequence listing submitted in computer readable form as XML file 10142US03_Sequence, created on Nov. 29, 2023 and containing 429,198 bytes. FIELD OF THE INVENTION The present invention relates to methods for treating an inflammatory condition comprising administering to a subject in need thereof a therapeutically effective amount of an interleukin-33 (IL-33) antagonist alone or in combination with an interleukin-4 (IL-4) antagonist. More specifically, the present invention relates to treating inflammatory or obstructive lung diseases or disorders by administering a therapeutically effective amount of an interleukin-33 (IL-33) antibody alone or in combination with an interleukin-4R (IL-4R) antibody. BACKGROUND Inflammation is initiated as a protective response by the host, but it can often result in systemic pathologies. Inflammatory lung diseases such as asthma, allergy and chronic obstructive pulmonary disease (COPD) are increasing in developed countries, resulting in great consequences to healthcare costs. Several inflammatory cells and their mediators participate in the development and progression of these diseases. In certain cases, these diseases reflect the outcome of type 2 immunity, which is characterized by the infiltration of tissues with eosinophils, basophils, mast cells, CD4+ T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILC2s), interleukin-4 (IL-4) and/or IL-13 induced macrophages, as well as by an elevation in serum IgE and by an increase in the cytokines IL-4, IL-5, IL-9 and IL-13. One cytokine believed to play a role in inflammatory lung diseases is interleukin-33 (IL-33), a proinflammatory cytokine released by damaged epithelial tissue in response to insults such as allergens, viruses, or smoke. IL-33 is a member of the interleukin-1 (IL-1) family that potently drives production of T helper-2 (Th2)-associated cytokines (e.g., IL-4). IL-33 is expressed by a wide variety of cell types, including fibroblasts, mast cells, dendritic cells, macrophages, osteoblasts, endothelial cells, and epithelial cells. Interleukin-33 (IL-33) is a ligand for ST2 (sometimes referred to as “suppression of tumorigenicity 2”), a toll-like/interleukin-1 receptor super-family member, which associates with an accessory protein, IL-1RAcP (“Interleukin-1 receptor accessory protein”, for reviews, see, e.g., Kakkar and Lee, Nature Reviews—Drug Discovery 7(10):827-840 (2008), Schmitz et al., Immunity 23:479-490 (2005); Liew et al., Nature Reviews—Immunology 10:103-110 (2010); US 2010/0260770; US 2009/0041718). Upon activation of ST2/IL-1RAcP by IL-33, a signaling cascade is triggered through downstream molecules such as MyD88 (myeloid differentiation factor 88) and TRAF6 (TNF receptor associated factor 6), leading to activation of NFκB (nuclear factor-κB), among others. IL-33 signaling has been implicated as a factor in a variety of diseases and disorders, including the inflammatory lung diseases disclosed herein. (Liew et al., Nature Reviews—Immunology 10:103-110 (2010)). Inhibitors of IL-33 signaling have been described in, for example, U.S. Pat. Nos. 9,453,072; 8,187,596; US2013/17373761; US2014/0212412; US2014/0271658; US2014/0271642; US2014/0004107; WO2015/099175; WO2015/106080; WO2011/031600; WO2014/164959; WO2014/152195; WO2013/165894; WO2013/173761; EP1725261; EP10815921A1; and EP2850103A2. Interleukin-4 (IL-4, also known as B cell stimulating factor or BSF-1) has also been implicated as a key cytokine that drives allergic and T helper cell type 2 (Th2) polarized inflammatory processes. IL-4 has been shown to possess a broad spectrum of biological activities, including growth stimulation of T cells, mast cells, granulocytes, megakaryocytes and erythrocytes. IL-4 induces the expression of class II major histocompatibility complex molecules in resting B cells, and enhances the secretion of IgE and IgG1 isotypes by stimulated B cells. The biological activities of IL-4 are mediated by specific cell surface receptors for IL-4. Human IL-4 receptor alpha (hIL-4R) (SEQ ID NO: 347) is described in, for example, U.S. Pat. Nos. 5,599,905, 5,767,065, and 5,840,869. Antibodies to hIL-4R are described in U.S. Pat. Nos. 5,717,072, 7,186,809 and 7,605,237. Methods for using antibodies to hIL-4R are described in U.S. Pat. Nos. 5,714,146; 5,985,280; 6,716,587 and 9,290,574. Current therapies for treati